INTERLEUKIN-12 INHIBITS GRAFT-VERSUS-HOST DISEASE THROUGH AN FAS-MEDIATED MECHANISM ASSOCIATED WITH ALTERATIONS IN DONOR T-CELL ACTIVATION AND EXPANSION

We have recently made the paradoxical observation that a single inject ion of recombinant murine interleukin-12 (IL-12) on the day of bone ma rrow transplantation (BMT) inhibits graft-versus-host disease (GVHD) i n lethally irradiated mice receiving fully major histocompatability co mplex (MHC)mismatched bone marrow and spleen cells. We have now examin ed the mechanism of this effect of IL-12 on acute GVHD, By day 4 post- BMT, IL-12-treated mice showed marked reductions in splenic donor CD4( +) and CD8(+) T cells compared with GVHD controls. Expression of the e arly activation markers IL-2R alpha chain (CD25) and CD69 on splenic d onor CD4(+) cells was considerably higher at early time points (36 and 72 hours post-BMT) in IL-12-treated mice compared with GVHD controls. However, the later, GVHD-associated increase in CD25 and very late an tigen-4 (VLA-4) expression on donor T cells was greatly depressed in I L-12-protected mice compared with GVHD controls. The marked GVHD-assoc iated expansion of host-reactive T helper cells by day 4 was also comp letely inhibited in the IL-12-treated group. Expression of Fas was inc reased on donor CD4 cells of IL-12-treated mice compared with those of controls on days 3 through 7 post-BMT. Furthermore, the ability of IL -12 to protect against GVHD was at least partially dependent on the ab ility of donor cells to express functional Fas molecules, We conclude that IL-12 treatment at the time of BMT markedly perturbs the activati on of alloreactive donor CD4(+) T cells that play a critical role in t he pathogenesis of acute GVHD, We hypothesize that these perturbations culminate in Fas-dependent apoptosis of donor T cells, thus impeding their expansion and their GVHD-promoting activity. (C) 1998 by The Ame rican Society of Hematology.